The present invention relates to a method intended for the separation of a mixture of two optical isomers, by means of a simulated mobile bed (SMB) using a chiral stationary phase and an achiral eluent.
It is known that, in chiral chromatography, porous solids are used with which a mixture of two optical isomers dissolved in a fluid, or a mixture of fluids, is placed in contact, which present different properties of adsorption having regard to each of the optical isomers. These porous solids are called chiral stationary phases or CSPs.
Most of the time, chiral chromatography methods employ a simple column, filled with chiral stationary phase, through which a fluid, called eluent, passes. At regular intervals of time, there is injected into the stream of eluent the mixture of the optical isomers to be separated, which is dissolved in an appropriate fluid, which may in particular be constituted by the eluent itself The mixture of optical isomers is thus entrained in the column and, at the outlet thereof, the optical isomer least adsorbed is, in known manner, recovered before the most adsorbed optical isomer.
In order to ensure separation of two optical isomers, it has also been proposed to employ a so-called xe2x80x9csimulated mobile bedxe2x80x9d technique. The simulated mobile bed is an old concept which has been used since the 1960s for the large-scale separation of the isomers of xylene, n-alkanes, iso-alkanes or fructose and glucose. Since 1990, it has been used in the domain of fine chemistry, and especially for the separation of optical isomers. Concerning this latter category of products, the simulated mobile bed is described as being an effective method for simultaneously obtaining two very pure optical isomers. Purities that may exceed 99.5% have thus been obtained. This technique has been described in particular in U.S. Pat. Nos. 2,985,589, 4,402,832, 4,498,991 and 5,126,055.
It is known that a simulated mobile bed is constituted by a given number of columns containing a stationary phase which are connected together in series. A solution, constituted by the mixture of the compounds to be separated dissolved in an appropriate fluid, called charge, and an eluent, are injected continuously at the inlet of two different columns. At the level of a column located downstream of the column where the charge is injected, a flux, called raffinate, is collected, which contains the enantiomer less immobilised in the eluent and, upstream of the column where the charge is injected, a flux, called discharge, is collected, which contains the enantiomer more immobilised in the eluent. In this way, a plurality of work zones are defined, each comprising a point of injection and a point of drawing-off.
The points of injection and of drawing-off are offset at regular intervals of time in the direction of flow. The interval of time located between two offsets of the points of injection/drawing-off is called a period.
Principally, two configurations of simulated mobile bed have been described: a simulated mobile bed with four zones and a simulated mobile bed with three zones (cf. Ruthven and Ching 1989 xe2x80x9cChemical Engineering Sciencexe2x80x9d).
A major drawback of this type of technique is that, beyond a given productivity, called maximum productivity of the installation, any increase in the amount of charge is made to the detriment of the purity of the products obtained, this limiting the development of the techniques of this type.
Applicants have established that it was possible to exceed the maximum productivity obtained in the simulated mobile beds functioning in accordance with the methods of the prior state of the art, while conserving the purity of one or the other of the separated enantiomers. In order to achieve such a result, Applicants have established that appropriate modifications of the functions exerted at the level of the different zones of the simulated mobile bed as well as of the flowrates employed were necessary.
The tests carried out by Applicants have thus led them to establish that, in order to improve the productivity of the installation, the amount of charge had, of course, to be increased but that, in order to obtain results likewise interesting from the standpoint of purity of the separated enantiomers, such increase had to be combined with an appropriate modification of the discharge flow.
The present invention thus has for its object to propose a method of separation of optical isomers which makes it possible to improve the yield of the methods according to the prior state of the art, while conserving the purity of one of the isomers obtained, and even by increasing the latter.
The present invention thus relates to a method of separation of a mixture of two optical isomers adapted to be more or less immobilised in a chiral stationary phase, this method being of the type employing a simulated mobile bed, constituted by an assembly of columns disposed in series, filled with a chiral stationary phase, which are divided into at least three successive zones, namely a first zone at the inlet of which an eluent is injected and at the outlet of which a flux, called discharge flux, principally containing the more immobilised enantiomer, is drawn off, a second zone at the inlet of which said mixture is injected, and a third zone at the outlet of which a flux, called raffinate flux, principally containing the less immobilized enantiomer is drawn off, characterized in that, with respect to a reference state in which: a) the optical isomer more immobilised in the stationary phase is completely desorbed in the first zone and is completely adsorbed in the third zone and where the optical isomer less immobilised in the stationary phase is completely desorbed in the second zone, and b) the amount of charge is maximum,
the amount of charge injected is greater than that of the reference state,
the discharge flow is greater than that of the reference state if it is desired at least to preserve the purity of the less immobilised enantiomer, or the discharge flow is less than that of the reference state if it is desired at least to preserve the purity of the more immobilised enantiomer.
In one form of embodiment of the invention, the amount of charge injected is rendered greater than that of the reference state by playing on the volumic flowrate of the charge.
In another form of embodiment of the invention, the amount of charge injected is rendered greater than that of the reference state by playing on the concentration of the charge.
Preferably, and as set forth in the form of embodiment described hereinafter, the simulated mobile bed comprises four zones, the fourth zone being located downstream of the point of drawing off of raffinate and, in the reference state, the optical isomer less immobilised in the stationary phase is completely adsorbed in this fourth zone. The outlet of the last zone is possibly connected to the inlet of the first zone.
Furthermore, it has been established that, at first approximation, the factor of increase of amount of charge, i.e. the ratio of the amount of charge injected according to the invention with respect to the amount of charge injected in the reference state, for narrow intervals of this factor, and the factor of correction of discharge flow, i.e. the ratio of the discharge flow with respect to the ratio of the discharge flow in the reference state, are bound by a substantially linear mathematical relationship. It will be noted that, under these conditions, the slope of the curve representing the variation of the factor of correction of discharge flow as a function of the variations of the factor of increase of amount of charge varies inversely with respect to the value of the selectivity of the stationary phase used.
More precisely, it has been established that the factor of increase of the amount of charge and the factor of correction of discharge flow are bound by a linear relationship expressing the ratio of the factor of increase of the amount of charge with respect to the factor of correction of discharge flow decreased by a value of one, as a function of the factor of correction of charge flow decreased by a value of one. It has also been established that the factor of proportionality of said linear relationship includes the value of the selectivity of the stationary phase used. More precisely, said factor of proportionality is substantially equal to a quarter of the value of the selectivity.
The present invention is applicable to a simulated mobile bed system constituted by a given number of columns disposed in series in zones allocated different functionalities. The mixture of the optical isomers that it is desired to separate and one or two achiral desorbents are continuously introduced in the columns containing an optically active stationary phase. Two streams containing the enriched optical isomers are extracted continuously from the line of columns. The charge and the desorbent or desorbents are injected via points of injection which are offset periodically in the direction of displacement of the eluent. The two flows of enriched optical isomers are recovered in periodically offset points of recovery.
A form of embodiment of the present invention will be described hereinafter by way of example, with reference to the accompanying drawings, in which: